The insulin-like growth factor-I plays a role in most functions of the body. it is produced by the liver, from where it reaches the circulation, and by most non-hepatic tissues where it acts locally. To study the roles of circulating versus paracrine effects of IGF-I we gene-deleted the IGF-I from the liver using the cre/loxP system. Thess mice showed a marked reduction in circulating IGF-I but no obvious phenotype. When they were crossed with mice with an acid labile subunit gene-deletion, the circulating levels fells further and these mice showed growth retardation and a reduction in bone density suggesting an important role for circulating "endocrine" IGF-I. What remains to be determined are the roles for paracrine IGF-I. Liver IGF-I-deleted mice also showed a delayed onset and growth and metastases of an orthotopic colon cancer introduced by implanting the tumor onto the cecum. In a second model, DMBA -induced breast cancer and a gentically introduced breast cancer (SV40TAg mice) also showed delayed onset of tumor appearance, reduced growth and fewer tumors in the liver IGF-I-deleted mice. These results suggest that circulating IGF-I levels maybe important in the risk for cancer growth and metastases.